EP0120276A1 - Substituted diazolylalkyl or triazolylalkyl carbinols, process for their preparation and their use as antimycotic compounds - Google Patents

Substituted diazolylalkyl or triazolylalkyl carbinols, process for their preparation and their use as antimycotic compounds Download PDF

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Publication number
EP0120276A1
EP0120276A1 EP84101710A EP84101710A EP0120276A1 EP 0120276 A1 EP0120276 A1 EP 0120276A1 EP 84101710 A EP84101710 A EP 84101710A EP 84101710 A EP84101710 A EP 84101710A EP 0120276 A1 EP0120276 A1 EP 0120276A1
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carbon atoms
alkyl
phenyl
alk
chain
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German (de)
French (fr)
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EP0120276B1 (en
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Hans-Ludwig Dr. Elbe
Erik Dipl.-Ing. Regel
Karl Heinz Prof. Dr. Büchel
Klaus Dr. Schaller
Manfred Dr. Plempel
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to new substituted diazolylalkyl carbinols, a process for their preparation and their use as antifungals.
  • the compounds of formula (I) optionally have two asymmetric carbon atoms. In this case, they can exist in two geometric isomer forms.
  • substituted diazolylalkylcarbinols of the formula (I) are obtained if azolyloxiranes of the formula in which B, R, X and Y have the meaning given above, with azoles of the formula in which A has the meaning given above, in the presence of a diluent and optionally in the presence of a base.
  • the new substituted diazolylalkyl carbinols of the formula (I) have strong antifungal properties.
  • the new substituted diazolylalkyl carbinols of the formula (I) are interesting intermediates.
  • the compounds of the general formula (I) on the hydroxyl group are converted into the corresponding ethers in a conventional manner.
  • Acyl halides or carbamoyl chlorides can be obtained in a manner known in principle, acyl or carbamoyl derivatives of the compounds of the general formula (I).
  • Preferred compounds according to the invention are also addition products of acids and those substituted diazolylalkylcarbinols of the formula (I) in which the substituents A, B, X, Y and R have the meanings which have already been mentioned preferably for these substituents.
  • the acids that can be added preferably include hydrohalic acids, e.g. Hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid, and also sulfonic acids, such as o-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.
  • hydrohalic acids e.g. Hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid
  • Formula (II) provides a general definition of the azolyl oxiranes to be used as starting materials for carrying out the process according to the invention.
  • B, R, X and Y preferably represent the meanings which have already been mentioned for these substituents in connection with the description of the substances of the formula (I) according to the invention.
  • the oxiranes of the formula (II) obtained in this way can optionally be reacted directly without isolation.
  • Inert organic solvents are suitable as diluents for the process for the preparation of the azolyl ketones of the formula (IVa). These preferably include ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile and propionitrile; Alcohols such as ethanol or isopropanol; Ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as toluene, benzene or chlorobenzene; Formamides such as dimethylformamide and halogenated hydrocarbons such as methylene chloride.
  • ketones such as acetone and methyl ethyl ketone
  • Nitriles such as acetonitrile and propionitrile
  • Alcohols such as ethanol or isopropanol
  • Ethers such as tetrahydrofuran or dioxane
  • aromatic hydrocarbons such as toluene, benzene or chlorobenz
  • the process for the preparation of the azolyl ketones of the formula (IVa) is carried out in the presence of an acid binder.
  • an acid binder You can add all commonly used inorganic and organic acid binders, such as Alkali carbonates, for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or such as lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N, N-dimethylcyclohexylamine, dicyclohexylamine, N, N-dimethylbenzylamine, furthermore pyridine and diazabicyclooctane. An appropriate excess of azole is preferably used.
  • reaction temperatures can be varied within a wide range in the process for the preparation of the azolyl ketones of the formula (IVa). Generally one works between about 20 to 150 ° C, preferably at 40 to 100 ° C.
  • the new azolyl ketones of the formula (IVa) are not only interesting intermediates, but also have good antifungal properties. Azolyl ketones of the formula (IVa) can also be used as crop protection agents in certain application rates.
  • Suitable diluents for the process according to the invention are organic solvents which are inert under the reaction conditions. These preferably include alcohols, e.g. Ethanol, methoxyethanol or propanol; Ketones, e.g. 2-butanone; Nitriles, e.g. Acetonitrile; Esters such as B. ethyl acetate; Ethers such as B. dioxane; aromatic hydrocarbons such as B. benzene and toluene; or amides, such as. B. Dimethylformamide.
  • alcohols e.g. Ethanol, methoxyethanol or propanol
  • Ketones e.g. 2-butanone
  • Nitriles e.g. Acetonitrile
  • Esters such as B. ethyl acetate
  • Ethers such as B. dioxane
  • aromatic hydrocarbons such as B. benzene and toluene
  • amides
  • Suitable bases for the reaction according to the invention are all commonly used inorganic and organic bases. These preferably include alkali metal carbonates, such as, for. B. sodium and potassium carbonate; alkali hydroxides, such as sodium hydroxide; Alkali alcoholates, such as sodium and potassium methylate and ethylate; Alkali hydrides such as sodium hydride; as well as lower tertiary alkylamines, cycloalkylamines and aralkylamines, such as in particular triethylamine.
  • alkali metal carbonates such as, for. B. sodium and potassium carbonate
  • alkali hydroxides such as sodium hydroxide
  • Alkali alcoholates such as sodium and potassium methylate and ethylate
  • Alkali hydrides such as sodium hydride
  • lower tertiary alkylamines, cycloalkylamines and aralkylamines such as in particular triethylamine.
  • reaction temperatures can be varied within a substantial range when carrying out the process according to the invention. In general, temperatures between 0 and 200 ° C, preferably between 60 and 150 ° C.
  • reaction temperatures can be varied within a substantial range when carrying out the oxidation according to the invention. Generally one works between about -50 to 100 ° C, preferably between -30 and 80 ° C.
  • the acid addition salts of the compounds of formula (I) can be easily obtained by conventional salt formation methods, e.g. by dissolving a compound of formula (I) in a suitable inert solvent and adding the acid, e.g. Hydrochloric acid can be obtained and in a known manner, e.g. by filtering, isolated and optionally cleaned by washing with an organic solvent.
  • the compounds of formula (I) which can be used according to the invention and their acid addition salts have antimicrobial, in particular strong antifungal, effects. They have a very broad antimycotic activity spectrum in particular against dermatophytes and yeasts as well as bi - phasic mushrooms, zBitch Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Torulopsis species such as Torulopsis glabrata. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and methods for producing these preparations.
  • the present invention also includes pharmaceutical preparations in dosage units.
  • the preparations in the form of individual parts e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose.
  • the dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.
  • a single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.
  • Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.
  • Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.
  • Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) moisture retention agents, e.g. Glycerin, (d) disintegrant, e.g. Agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g.
  • fillers and extenders e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica
  • binders e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone
  • moisture retention agents e.g. Glycer
  • quaternary ammonium compounds (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • wetting agents e.g. Cetyl alcohol, glycerol monostearate
  • adsorbent e.g. Kaolin and bentonite
  • lubricants e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).
  • the tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding materials, e.g. Polymer substances and waxes can be used.
  • Embedding materials e.g. Polymer substances and waxes can be used.
  • the active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.
  • suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example K akaofat and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • water-soluble or water-insoluble carriers for example polyethylene glycols, fats, for example K akaofat and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.
  • ointments, pastes, creams or gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide or mixtures of these substances.
  • carriers e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide or mixtures of these substances.
  • Powders and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, sprays can additionally contain the usual blowing agents e.g. Contain chlorofluorocarbons.
  • active ingredient e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances
  • sprays can additionally contain the usual blowing agents e.g. Contain chlorofluorocarbons.
  • solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially tree woolen oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.
  • solvents such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-but
  • solutions and emulsions can also be in sterile and blood isotonic form.
  • suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • liquid diluents e.g. Water, ethyl alcohol, propylene glycol
  • suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.
  • the formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Contain saccharin.
  • the therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.
  • the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.
  • the pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
  • the present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in human and veterinary medicine for preventing, ameliorating and / or curing the diseases mentioned above.
  • the active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.
  • the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.
  • the dosages mentioned may be necessary to deviate from the dosages mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease Type of preparation and application of the drug as well as the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded.
  • the determination of the required optimal dosage and type of application of the active ingredients can easily be made by any specialist on the basis of his specialist knowledge.
  • Forms A and B The two possible geometric isomers According to Example 1 and according to the specified process conditions, the following intermediates of the general formula receive.
  • the incubation temperature was 20 ° C, the incubation period was 24 to 96 hours for yeasts and 96 hours for dermatophytes and molds.
  • mice of the type SPF-CF 1 were infected intravenously with 1-2 x 10 6 logarthmically growing Candida cells, which are suspended in physiological saline. One hour before and seven hours after the infection, the animals are treated orally with 10-50 mg / kg body weight of the preparations.

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Abstract

1. Substituted di- or triazolylalkyl-carbinols of the general formula see diagramm : EP0120276,P20,F1 in which A represents a nitrogen atom or the CH group ; B represents a nitrogen atom or the CH group ; X represents hydrogen and straight-chain or branched alkyl with 1 to 6 carbon atoms ; Y represents straight-chain or branched alkyl with 1 to 6 carbon atoms ; and, if X represents hydrogen, also straight-chain or branched alkenyl and alkinyl with in each case 3 to 6 carbon atoms and benzyl which is optionally mono- to trisubstituted in the phenyl part by identical or different substituents, substituents which may mentioned being : halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro and cyano ; R represents phenyl which is optionally mono- to tri-substituted by identical or different substituents, preferred substituents which may be mentioned being : halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro, cyano, hydroxyl, hydroxycarbonyl with 1 to 4 carbon atoms in the alkyl part, hydroximinoalkyl with 1 to 4 carbon atoms, alkoximinoalkyl with 1 to 4 carbon atoms in each alkyl part, and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by halogen and/or alkyl with 1 to 2 carbon atoms ; R furthermore preferably represents the grouping see diagramm : EP0120276,P20,F2 wherein Alk**1 represents straight-chain or branched alkyl with 1 to 4 carbon atoms ; Alk**2 represents straight-chain or branched alkyl with 1 to 4 carbon atoms ; Alk**1 and Alk**2, together with the carbon atom to which they are bonded, represent a 3- to 7-centered cycloaliphatic ring ; and R**1 represents, straight-chain or branched alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 4 carbon atoms and phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxy, phenylthio, phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, phenylthioalkyl with 1 to 4 carbon atoms in the alkyl part, benzyloxy and benzylthio, each of which is optionally mono- to trisubstituted in the phenyl part by identical or different substituents, preferred possible substituents being the phenyl substituents alreadly mentioned for R.

Description

Die vorliegende Erfindung betrifft neue substituierte Diazolylalkyl-carbinole, ein Verfahren zu ihrer Herstellung und ihre Verwendung als Antimykotika.The present invention relates to new substituted diazolylalkyl carbinols, a process for their preparation and their use as antifungals.

Es ist bereits bekannt geworden, daß bestimmte Diazolyl-Derivate antimykotische Eigenschaften aufweisen.It has already become known that certain diazolyl derivatives have antifungal properties.

Es wurden neue substituierte Diazolylalkyl-carbinole der allgemeinen Formel

Figure imgb0001
in welcher

  • A für ein Stickstoffatom oder die CH-Gruppe steht,
  • B für ein Stickstoffatom oder die CH-Gruppe steht,
  • X für Wasserstoff oder Alkyl steht,
  • Y für Alkyl steht, sowie auch für Alkenyl, Alkinyl oder gegebenenfalls substituiertes Benzyl steht, wenn X für Wasserstoff steht und
  • R für gegebenenfalls substituiertes Phenyl und die Gruppierung
    Figure imgb0002
    steht, wobei
  • Alk 1 für Alkyl steht,
  • Alk2 für Alkyl steht, oder
  • Alk und Alk2 gemeinsam für einen cycloaliphatischen Ring stehen und
  • R für Alkyl, Alkenyl oder für jeweils gegebenenfalls substituiertes Phenyl, Phenylalkyl, Phenoxy, Phenylthio, Phenoxyalkyl, Phenylthioalkyl, Benzyloxy oder Benzylthio steht, und deren physiologisch verträgliche Säureadditions-Salze gefunden.
There have been new substituted diazolylalkyl carbinols of the general formula
Figure imgb0001
 in which
  • A represents a nitrogen atom or the CH group,
  • B represents a nitrogen atom or the CH group,
  • X represents hydrogen or alkyl,
  • Y stands for alkyl, and also stands for alkenyl, alkynyl or optionally substituted benzyl, if X stands for hydrogen and
  • R represents optionally substituted phenyl and the grouping
    Figure imgb0002
     stands where
  • Alk 1 represents alkyl,
  • Alk 2 represents alkyl, or
  • Alk and A lk 2 together represent a cycloaliphatic ring and
  • R represents alkyl, alkenyl or optionally substituted phenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy or benzylthio, and their physiologically acceptable acid addition salts found.

Die Verbindungen der Formel (I) besitzen gegebenenfalls zwei asymmetrische Kohlenstoffatome. In diesem Falle können sie in zwei geometrischen Isomerenformen vorliegen.The compounds of formula (I) optionally have two asymmetric carbon atoms. In this case, they can exist in two geometric isomer forms.

Weiterhin wurde gefunden, daß man die substituierten Diazolylalkyl-carbinole der Formel (I) erhält, wenn man Azolyl-oxirane der Formel

Figure imgb0003
in welcher B, R, X und Y die oben angegebene Bedeutung haben, mit Azolen der Formel
Figure imgb0004
in welcher A die oben angegebene Bedeutung hat, in Gegenwart eines Verdünnungsmittels und gegebenenfalls in Gegenwart einer Base umsetzt.It has also been found that the substituted diazolylalkylcarbinols of the formula (I) are obtained if azolyloxiranes of the formula
Figure imgb0003
 in which B, R, X and Y have the meaning given above, with azoles of the formula
Figure imgb0004
 in which A has the meaning given above, in the presence of a diluent and optionally in the presence of a base.

An die so erhaltenen Verbindungen der Formel (I) kann gegebenenfalls anschließend eine Säure addiert werden.An acid can then optionally be added to the compounds of formula (I) thus obtained.

Die neuen substituierten Diazolylalkyl-carbinole der Formel (I) weisen starke antimykotischen Eigenschaften auf.The new substituted diazolylalkyl carbinols of the formula (I) have strong antifungal properties.

Außerdem sind die neuen substituierten Diazolylalkyl-carbinole der Formel (I) interessante Zwischenprodukte. So können z.B. die Verbindungen der allgemeinen Formel (I) an der Hydroxygruppe in üblicher Weise in die entsprechenden Ether überführt werden. Weiterhin können durch Umsetzung mit z.B. Acylhalogeniden oder Carbamoylchloriden in prinzipiell bekannter Weise Acyl- oder Carbamoyl-Derivate der Verbindungen der allgemeinen Formel (I) erhalten werden.In addition, the new substituted diazolylalkyl carbinols of the formula (I) are interesting intermediates. For example, the compounds of the general formula (I) on the hydroxyl group are converted into the corresponding ethers in a conventional manner. Furthermore, by implementation with e.g. Acyl halides or carbamoyl chlorides can be obtained in a manner known in principle, acyl or carbamoyl derivatives of the compounds of the general formula (I).

Außerdem können die Verbindungen der allgemeinen Formel (I), in denen R1 für jeweils gegebenenfalls substituiertes Phenylthio, Phenylthioalkyl oder Benzylthio steht, in üblicher Weise zu den entsprechenden SO- bzw. SOZ-Derivaten oxidiert werden.In addition, the compounds of the general formula ( I ) in which R 1 stands for optionally substituted phenylthio, phenylthioalkyl or benzylthio can be oxidized in a conventional manner to the corresponding SO or SO Z derivatives.

Die erfindungsgemäßen substituierten Diazolylalkylcarbinole sind durch die Formel (I) allgemein definiert. In dieser Formel stehen vorzugsweise

  • A für ein Stickstoffatom oder die CH-Gruppe;
  • B für ein Stickstoffatom oder die CH-Gruppe;
  • X für Wasserstoff und geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen;
  • Y für geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen; sowie für den Fall, daß X für Wasserstoff steht, auch für geradkettiges oder verzweigtes Alkenyl und Alkinyl mit jeweils 3 bis 6 Kohlenstoffatomen sowie für gegebenenfalls einfach bis dreifach gleich oder verschieden im Phenylteil substituiertes Benzyl, wobei als Substituenten genannt seien:
    • Halogen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy und Alkylthio mit jeweils 1 bis 4 Kohlenstoffatomen, Halogenalkyl, Halogenalkoxy und Halogenalkylthio mit jeweils 1 bis 2 Kohlenstoff- und 1 bis 5 gleichen oder verschiedenen Halogenatomen, wie vorzugsweise Fluor- und Chloratomen, Nitro-und Cyano;
  • R für gegebenenfalls einfach bis dreifach, gleich oder verschieden substituiertes Phenyl, wobei als Substituenten vorzugsweise genannt seien: Halogen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy und Alkylthio mit jeweils 1 bis 4 Kohlenstoffatomen, Halogenalkyl, Halogenalkoxy und Halogenalkylthio mit jeweils 1 bis 2 Kohlenstoff- und 1 bis 5 gleichen oder verschiedenen Halogenatomen, wie vorzugsweise Fluor- und Chloratomen, Nitro, Cyano, Hydroxy, Hydroxycarbonyl, Alkoxycarbonyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Hydroximinoalkyl mit 1 bis 4 Kohlenstoffatomen, Alkoximinoalkyl mit 1 bis 4 Kohlenstoffatomen in jedem Alkylteil, sowie jeweils gegebenenfalls durch Halogen und/oder Alkyl mit 1 bis 2 Kohlenstoffatomen substituiertes Phenyl, Phenoxy, Benzyl und Benzyloxy; R steht ferner vorzugsweise für die Gruppierung
    Figure imgb0005
    wobei
  • Alk1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht;
  • Alk2 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht;
  • Alk1 und Alk2 gemiensam mit dem Kohlenstoffatom, an das sie gebunden sind, für einen 3- bis 7-gliedrigen cycloaliphatischen Ring stehen; und
  • R 1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, für Alkenyl mit 2 bis 4 Kohlenstoffatomen, sowie für jeweils gegebenenfalls im Phenylteil einfach bis dreifach, gleich oder verschieden substituiertes Phenyl, Phenylalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Phenoxy, Phenylthio, Phenoxyalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Phenylthioalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Benzyloxy und Benzylthio steht, wobei als Substituenten vorzugsweise die bei R bereits genannten Phenylsubstituenten in Frage kommen.
Formula (I) provides a general definition of the substituted diazolylalkylcarbinols according to the invention. In this formula are preferably
  • A represents a nitrogen atom or the CH group;
  • B represents a nitrogen atom or the CH group;
  • X represents hydrogen and straight-chain or branched alkyl having 1 to 6 carbon atoms;
  • Y represents straight-chain or branched alkyl having 1 to 6 carbon atoms; and in the event that X represents hydrogen, also straight-chain or branched alkenyl and alkynyl each having 3 to 6 carbon atoms and for benzyl which is monosubstituted to trisubstituted identically or differently in the phenyl part, the following being mentioned as substituents:
    • Halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 4 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each having 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro and Cyano;
  • R represents phenyl which is monosubstituted to trisubstituted by identical or different substituents, the preferred substituents being: halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 4 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each with 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro, cyano, hydroxy, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, hydroximinoalkyl with 1 to 4 carbon atoms, alkoximinoalkyl with 1 up to 4 carbon atoms in each alkyl part, and in each case phenyl, phenoxy, benzyl and benzyloxy optionally substituted by halogen and / or alkyl having 1 to 2 carbon atoms; R also preferably represents the grouping
    Figure imgb0005
     in which
  • Alk 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms;
  • Alk 2 represents straight-chain or branched alkyl having 1 to 4 carbon atoms;
  • Alk 1 and Alk 2 together with the carbon atom to which they are attached represent a 3- to 7-membered cycloaliphatic ring; and
  • R 1 for straight-chain or branched alkyl having 1 to 6 carbon atoms, for alkenyl having 2 to 4 carbon atoms, and for phenyl, in the phenyl part in each case monosubstituted to trisubstituted in the same or different manner, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxy, phenylthio, Phenoxyalkyl having 1 to 4 carbon atoms in the alkyl part, phenylthioalkyl having 1 to 4 carbon atoms in the alkyl part, benzyloxy and benzylthio, the phenyl substituents already mentioned for R being preferred as substituents.

Besonders bevorzugt sind diejenigen Verbindungen der Formel (I), in denen

  • A für ein Stickstoffatom oder die CH-Gruppe steht;
  • B für ein Stickstoffatom oder die CH-Gruppe steht;
  • X für Wasserstoff und geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht;
  • Y für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht; sowie für den Fall, daß X für Wasserstoff steht, auch für Allyl, Methylallyl, Propargyl, Methylpropargyl oder für gegebenenfalls einfach bis zweifach, gleich oder verschieden im Phenylteil substituiertes Benzyl steht, wobei als Substituenten genannt seien: Fluor, Chlor, Brom, Methyl, Isopropyl, tert.-Butyl, Methoxy, Methylthio, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Nitro und Cyano;
  • für gegebenenfalls einfach bis zweifach, gleich oder verschieden substituiertes Phenyl steht, wobei als Substituenten genannt seien: Fluor, Chlor, Brom, Methyl, Isopropyl, tert.-Butyl, Methoxy, Methylthio, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Nitro, Cyano, Hydroxy, Hydroxycarbonyl, Methoxycarbonyl, Ethoxycarbonyl, Hydroximinomethyl, 1-Hydroximinoethyl, Methoximinomethyl, 1-Methoximinoethyl, sowie jeweils gegebenenfalls durch Fluor, Chlor, Methyl substituiertes Phenyl, Phenoxy, Benzyl und Benzyloxy; ferner R für die Gruppierung
    Figure imgb0006
    steht, wobei
  • Alk1 für Methyl oder Ethyl steht;
  • Alk2 für Methyl oder Ethyl steht;
  • Alk1 und Alk2 gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, für Cyclobutyl, Cyclopentyl oder Cyclohexyl stehen; und R für Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, Neopentyl, sowie für jeweils gegebenenfalls im Phenylteil einfach bis zweifach, gleich oder verschieden substituiertes Phenyl, Benzyl, Phenethyl, Phenoxy, Phenylthio, Phenoxymethyl, Phenoxyethyl, Phenylthiomethyl, Phenylthioethyl, Benzyloxy oder Benzylthio steht, wobei als Substituenten die bei R bereits genannten Phenylsubstituenten in Frage kommen.
Those compounds of the formula (I) in which
  • A represents a nitrogen atom or the CH group;
  • B represents a nitrogen atom or the CH group;
  • X represents hydrogen and straight-chain or branched alkyl having 1 to 4 carbon atoms;
  • Y represents straight-chain or branched alkyl having 1 to 4 carbon atoms; and in the event that X stands for hydrogen, also for allyl, methylallyl, propargyl, methylpropargyl or for benzyl which is substituted once or twice, identically or differently in the phenyl part, the following being mentioned as substituents: Fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro and cyano;
  • represents phenyl which is monosubstituted or disubstituted, identically or differently, where the following may be mentioned as substituents: fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, cyano, hydroxy, Hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroximinomethyl, 1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl, and in each case optionally substituted by fluorine, chlorine, methyl, phenyl, phenoxy, benzyl and benzyloxy; furthermore R for the grouping
    Figure imgb0006
     stands where
  • Alk 1 represents methyl or ethyl;
  • A lk 2 represents methyl or ethyl;
  • Alk 1 and Alk 2 together with the carbon atom to which they are attached represent cyclobutyl, cyclopentyl or cyclohexyl; and R for methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl, and for phenyl, benzyl, phenethyl, phenoxy, phenylthio, phenoxymethyl, phenoxyethyl, phenylthiomethyl optionally monosubstituted or disubstituted in the phenyl part in each case Phenylthioethyl, benzyloxy or benzylthio, where the phenyl substituents already mentioned for R are suitable as substituents.

Bevorzugte erfindungsgemäße Verbindungen sind auch Additionsprodukte aus Säuren und denjenigen substituierten Diazolylalkyl-carbinolen der Formel (I), in denen die Substituenten A, B, X, Y und R die Bedeutungen haben, die bereits vorzugsweise für diese Substituenten genannt wurden.Preferred compounds according to the invention are also addition products of acids and those substituted diazolylalkylcarbinols of the formula (I) in which the substituents A, B, X, Y and R have the meanings which have already been mentioned preferably for these substituents.

Zu den Säuren, die addiert werden können, gehören vorzugsweise Halogenwasserstoffsäuren, wie z.B. Chlorwasserstoffsäure und die Bromwasserstoffsäure, insbesondere die Chlorwasserstoffsäure, ferner Phosphorsäure, Salpetersäure, mono- und bifunktionelle Carbonsäuren und Hydroxycarbonsäuren, wie z.B. Essigsäure, Maleinsäure, Bernsteinsäure, Fumarsäure, Weinsäure, Zitronensäure, Salizylsäure, Sorbinsäure und Milchsäure, sowie Sulfonsäuren, wie o-Toluolsulfonsäure und 1,5-Naphthalindisulfonsäure.The acids that can be added preferably include hydrohalic acids, e.g. Hydrochloric acid and hydrobromic acid, especially hydrochloric acid, also phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid and lactic acid, and also sulfonic acids, such as o-toluenesulfonic acid and 1,5-naphthalenedisulfonic acid.

Verwendet man beispielsweise 2-(4-Chlorphenyl-2-L2-(1,2, 4-triazol-1-yl)-2-propy!7-oxiran und 1,2,4-Triazol als Ausgangsstoffe, so kann der Ablauf des erfindungsgemäßen Verfahren durch das folgende Formelschema wiedergegeben werden:

Figure imgb0007
If, for example, 2- (4-chlorophenyl-2-L2- (1,2, 4-triazol-1-yl) -2-propy! 7-oxirane and 1,2,4-triazole are used as starting materials, the process can be carried out of the invention Procedures can be represented by the following formula scheme:
Figure imgb0007

Die für die Durchführung des erfindungsgemäßen Verfahrens als Ausgangsstoffe zu verwendenden Azolyl-oxirane sind durch die Formel (II) allgemein definiert. In dieser Formel stehen B, R, X und Y vorzugsweise für die Bedeutungen, die bereits im Zusammenhang mit der Beschreibung der erfindungsgemäßen Stoffe der Formel (I) vorzugsweise für diese Substituenten genannt wurden.Formula (II) provides a general definition of the azolyl oxiranes to be used as starting materials for carrying out the process according to the invention. In this formula, B, R, X and Y preferably represent the meanings which have already been mentioned for these substituents in connection with the description of the substances of the formula (I) according to the invention.

Die Azolyl-oxirane der Formel (II) sind noch nicht bekannt. Sie können jedoch erhalten werden, indem man Azolyl-ketone der Formel

Figure imgb0008
in welcher B, R, X und Y die oben angegebene Bedeutung haben,
entweder

  • _) mit Dimethyloxosulfonium-methylid der Formel
    Figure imgb0009
    in an sich bekannter Weise in Gegenwart eines Verdünnungsmittels, wie beispielsweise Dimethylsulfoxid, bei Temperaturen zwischen 20°C und 80°C umsetzt (vgl. hierzu die Angaben in J. Am. Chem. Soc. 87, 1363-1364 (1965)),
    oder
  • ß) mit Trimethylsulfonium-methylsulfat der Formel
    Figure imgb0010
    in an sich bekannter Weise in Gegenwart eines inerten organischen Lösungsmittels, wie z.B. Acetonitril, und in Gegenwart einer Base, wie z.B. Natriummethylat, bei Temperaturen zwischen 0°C bis 60°C, vorzugsweise bei Raumtemperatur, umsetzt (vgl. auch die Angaben in Heterocycles 8, 397 (1977)).
The azolyl oxiranes of the formula (II) are not yet known. However, they can be obtained by using azolyl ketones of the formula
Figure imgb0008
 in which B, R, X and Y have the meaning given above,
either
  • _) with dimethyloxosulfonium methylide of the formula
    Figure imgb0009
     in a manner known per se in the presence of a diluent, such as, for example, dimethyl sulfoxide, at temperatures between 20 ° C. and 80 ° C. (cf. the details in J. Am. Chem. Soc. 87, 1363-1364 (1965)),
    or
  • ß) with trimethylsulfonium methyl sulfate of the formula
    Figure imgb0010
     in a manner known per se in the presence of an inert organic solvent, such as, for example, acetonitrile, and in the presence of a base, such as, for example, sodium methylate, at temperatures between 0 ° C. to 60 ° C., preferably at room temperature (cf. also the information in heterocycles 8, 397 (1977)).

Die so erhaltenen Oxirane der Formel (II) können gegebenenfalls ohne Isolierung direkt weiter umgesetzt werden.The oxiranes of the formula (II) obtained in this way can optionally be reacted directly without isolation.

Die Azolyl-ketone der Formel (IV) sind teilweise bekannt (vgl. beispielsweise DE-OS 2 431 407, DE-OS 2 610 022, DE-OS 2 628 470 und DE-OS 3 048 266). Noch nicht bekannt sind Azolyl-ketone der Formel

Figure imgb0011
in welcher

  • X1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht,
  • Y1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht und
  • B und R die oben angegebene Bedeutung haben.
Some of the azolyl ketones of the formula (IV) are known (cf. for example DE-OS 2 431 407, DE-OS 2 610 022, DE-OS 2 628 470 and DE-OS 3 048 266). Azolyl ketones of the formula are not yet known
Figure imgb0011
 in which
  • X 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms,
  • Y 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms and
  • B and R have the meaning given above.

Die Azolyl-ketone der Formel (IVa) werden erhalten, indem man Halogenketone der Formel

Figure imgb0012
in welcher

  • R, X und Y die oben angegebene Bedeutung haben und Hal für Halogen, insbesondere Chlor oder Brom steht,
    mit Azolen der Formel
    Figure imgb0013
    in welcher
  • B die oben angegebene Bedeutung hat,
  • in Gegenwart eines Verdünnungsmittels und in Gegenwart eines Säurebindemittels umsetzt.
The azolyl ketones of formula (IVa) are obtained by using halogen ketones of formula
Figure imgb0012
 in which
  • R, X and Y have the meaning given above and Hal represents halogen, especially chlorine or bromine,
    with azoles of the formula
    Figure imgb0013
     in which
  • B has the meaning given above,
  • in the presence of a diluent and in the presence of an acid binder.

Für das Verfahren zur Herstellung der Azolyl-ketone der Formel (IVa) kommen als Verdünnungsmittel inerte organische Lösungsmittel in Frage. Hierzu gehören vorzugsweise Ketone, wie Aceton und Methylethylketon; Nitrile, wie Acetonitril und Propionitril; Alkohole, wie Ethanol oder Isopropanol; Ether, wie Tetrahydrofuran oder Dioxan; aromatische Kohlenwasserstoffe, wie Toluol, Benzol oder Chlorbenzol; Formamide, wie Dimethylformamid und halogenierte Kohlenwasserstoffe, wie Methylenchlorid.Inert organic solvents are suitable as diluents for the process for the preparation of the azolyl ketones of the formula (IVa). These preferably include ketones such as acetone and methyl ethyl ketone; Nitriles such as acetonitrile and propionitrile; Alcohols such as ethanol or isopropanol; Ethers such as tetrahydrofuran or dioxane; aromatic hydrocarbons such as toluene, benzene or chlorobenzene; Formamides such as dimethylformamide and halogenated hydrocarbons such as methylene chloride.

Das Verfahren zur Herstellung der Azolyl-ketone der Formel (IVa) wird in Gegenwart eines Säurebindemittels vorgenommen. Man kann alle üblicherweise verwendbaren anorganischen und organischen Säurebinder zugeben, wie Alkalicarbonate, beispielsweise Natriumcarbonat, Kaliumcarbonat und Natriumhydrogencarbonat, oder wie niedere tertiäre Alkylamine, Cycloalkylamine oder Aralkylamine, beispielsweise Triethylamin, N,N-Dimethylcyclohexylamin, Dicyclohexylamin, N,N-Dimethylbenzylamin, weiterhin Pyridin und Diazabicyclooctan. Vorzugsweise verwendet man einen entsprechenden Überschuß an Azol.The process for the preparation of the azolyl ketones of the formula (IVa) is carried out in the presence of an acid binder. You can add all commonly used inorganic and organic acid binders, such as Alkali carbonates, for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or such as lower tertiary alkylamines, cycloalkylamines or aralkylamines, for example triethylamine, N, N-dimethylcyclohexylamine, dicyclohexylamine, N, N-dimethylbenzylamine, furthermore pyridine and diazabicyclooctane. An appropriate excess of azole is preferably used.

Die Reaktionstemperaturen können beim Verfahren zur Herstellung der Azolyl-ketone der Formel (IVa) in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man zwischen etwa 20 bis 150°C, vorzugsweise bei 40 bis 100°C.The reaction temperatures can be varied within a wide range in the process for the preparation of the azolyl ketones of the formula (IVa). Generally one works between about 20 to 150 ° C, preferably at 40 to 100 ° C.

Bei der Durchführung des Verfahrens zur Herstellung der Azolyl-ketone der Formel (IVa) setzt man auf 1 Mol Halogenketon der Formel (VIII) vorzugsweise 1 bis 4 Mol Azol und 1 bis 4 Mol Säurebinder ein. Die Isolierung der Azolylketone der Formel (IVa) erfolgt in üblicher Art und Weise.When carrying out the process for the preparation of the azolyl ketones of the formula (IVa), 1 to 4 mol of azole and 1 to 4 mol of acid binder are preferably employed per 1 mol of halogen ketone of the formula (VIII). The azolyl ketones of the formula (IVa) are isolated in the customary manner.

Die Halogenketone der Formel (VII) sind teilweise bekannt (vgl. Synth. Commun. 12 (1982), S. 261-266), bzw. können sie in allgemein bekannter Art und Weise erhalten werden, indem man z.B. die entsprechenden Ketone der Formel

Figure imgb0014
in welcher

  • R, X1und Y die oben angegebene Bedeutung haben, mit Chlor oder Brom in Gegenwart eines inerten organischen Lösungsmittels, wie beispielsweise chlorierten Kohlenwasserstoffen, bei Raumtemperatur umsetzt; oder mit üblichen Chlorierungsmitteln, wie beispielsweise Sulfurylchlorid, bei Temperaturen zwischen 20 und 60°C umsetzt.
The halogen ketones of the formula (VII) are known in some cases (cf. Synth. Commun. 12 (1982), pp. 261-266), or they can be obtained in a generally known manner by, for example, the corresponding ketones of the formula
Figure imgb0014
 in which
  • R , X1 and Y have the meaning given above, with chlorine or bromine in the presence of an inert organic solvent, such as chlorinated hydrocarbons, at room temperature; or with conventional chlorinating agents, such as sulfuryl chloride, at temperatures between 20 and 60 ° C.

Die neuen Azolyl-ketone der Formel (IVa) stellen nicht nur interessante Zwischenprodukte dar, sondern zeigen auch selbst gute antimykotische Eigenschaften. In bestimmten Aufwandmengen können Azolyl-ketone der Formel (IVa) auch als Pflanzenschutzmittel eingesetzt werden.The new azolyl ketones of the formula (IVa) are not only interesting intermediates, but also have good antifungal properties. Azolyl ketones of the formula (IVa) can also be used as crop protection agents in certain application rates.

Als Verdünnungsmittel kommen für das erfindungsgemäße Verfahren unter den Reaktionsbedingungen inerte organische Lösungsmittel in Frage. Hierzu gehören vorzugsweise Alkohole, wie z.B. Ethanol, Methoxyethanol oder Propanol; Ketone, wie z.B. 2-Butanon; Nitrile, wie z.B. Acetonitril; Ester, wie z. B. Ethylacetat; Ether, wie z. B. Dioxan; aromatische Kohlenwasserstoffe, wie z. B. Benzol und Toluol; oder Amide, wie z. B. Dimethylformamid.Suitable diluents for the process according to the invention are organic solvents which are inert under the reaction conditions. These preferably include alcohols, e.g. Ethanol, methoxyethanol or propanol; Ketones, e.g. 2-butanone; Nitriles, e.g. Acetonitrile; Esters such as B. ethyl acetate; Ethers such as B. dioxane; aromatic hydrocarbons such as B. benzene and toluene; or amides, such as. B. Dimethylformamide.

Als Basen kommen für die erfindungsgemäße Umsetzung alle üblicherweise verwendbaren anorganischen und organischen Basen in Betracht, Hierzu gehören vorzugsweise Alkalicarbonate, wie z. B. Natrium- und Kaliumcarbonat; Alkalihydroxide, wie z.B. Natriumhydroxid; Alkalialkoholate, wie z.B. Natrium- und Kalium-methylat und -ethylat; Alkalihydride, wie z.B. Natriumhydrid; sowie niedere tertiäre Alkylamine, Cycloalkylamine und Aralkylamine, wie insbesondere Triethylamin.Suitable bases for the reaction according to the invention are all commonly used inorganic and organic bases. These preferably include alkali metal carbonates, such as, for. B. sodium and potassium carbonate; alkali hydroxides, such as sodium hydroxide; Alkali alcoholates, such as sodium and potassium methylate and ethylate; Alkali hydrides such as sodium hydride; as well as lower tertiary alkylamines, cycloalkylamines and aralkylamines, such as in particular triethylamine.

Die Reaktionstemperaturen können bei der Durchführung des erfindungsgemäßen Verfahrens in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man bei Temperaturen zwischen 0 und 200°C, vorzugsweise zwischen 60 und 150°C.The reaction temperatures can be varied within a substantial range when carrying out the process according to the invention. In general, temperatures between 0 and 200 ° C, preferably between 60 and 150 ° C.

Bei der Durchführung des erfindungsgemäßen Verfahrens setzt man vorzugsweise auf 1 Mol Oxiran der Formel (II) 1 bis 2 Mol Azol der Formel (III) und gegebenenfalls 1 bis 2 Mol Base ein; die Isolierung der Endprodukte erfolgt in allgemein üblicher Weise.When carrying out the process according to the invention, 1 to 2 moles of azole of the formula (III) and optionally 1 to 2 moles of base are preferably employed per mole of oxirane of the formula (II); The end products are isolated in a generally customary manner.

Die Reaktionstemperaturen können bei der Durchführung der erfindungsgemäßen Oxidation in einem größeren Bereich variiert werden. Im allgemeinen arbeitet man zwischen etwa -50 bis 100°C, vorzugsweise zeischen -30 und 80°C.The reaction temperatures can be varied within a substantial range when carrying out the oxidation according to the invention. Generally one works between about -50 to 100 ° C, preferably between -30 and 80 ° C.

Die erfindungsgemäßen Verbindungen der Formel (I) können auch erhalten werden, indem man Diazolyl-ketone der Formel

Figure imgb0015
in welcher

  • A, B, X und Y die oben angegebene Bedeutung haben,
    mit einem Grignard-Reagenz der Formel
    Figure imgb0016
    in welcher
  • R die oben angegebene Bedeutung hat und
  • Hal' für Halogen steht,
    in üblicher Weise unter den Bedingungen einer Grignard-Reaktion umsetzt;
    oder indem man Dihalogenalkanole der Formel
    Figure imgb0017
    in welcher
  • R, Hal, X und Y die oben angegebene Bedeutung haben,
    in üblicher Weise mit Azolen der Formel (III) umsetzt.
The compounds of formula (I) according to the invention can also be obtained by using diazolyl ketones of the formula
Figure imgb0015
 in which
  • A, B, X and Y have the meaning given above,
    with a Grignard reagent of the formula
    Figure imgb0016
     in which
  • R has the meaning given above and
  • Hal 'represents halogen,
    implemented in the usual way under the conditions of a Grignard reaction;
    or by using dihaloalkanols of the formula
    Figure imgb0017
     in which
  • R, Hal, X and Y have the meaning given above,
    reacted in the usual way with azoles of the formula (III).

Die Säureadditionssalze der Verbindungen der Formel (I) können in einfacher Weise nach üblichen Salzbildungsmethoden, z.B. durch Lösen einer Verbindung der Formel (I) in einem geeigneten inerten Lösungsmittel und Hinzufügen der Säure, z.B. Chlorwasserstoffsäure, erhalten werden und in bekannter Weise, z.B. durch Abfiltrieren, isoliert und gegebenenfalls durch Waschen mit einem organischen Lösungsmittel gereinigt werden.The acid addition salts of the compounds of formula (I) can be easily obtained by conventional salt formation methods, e.g. by dissolving a compound of formula (I) in a suitable inert solvent and adding the acid, e.g. Hydrochloric acid can be obtained and in a known manner, e.g. by filtering, isolated and optionally cleaned by washing with an organic solvent.

Die erfindungsgemäß verwendbaren Verbindungen der Formel (I) und ihre Säureadditions-Salze weisen antimikrobielle, insbesondere starke antimykotische Wirkungen auf. Sie besitzen ein sehr breites antimykotisches Wirkungsspektrum, insbesondere gegen Dermatophyten und Sproßpilze sowie bi-phasische Pilze, z.B.gegen Candida-Arten, wie Candida albicans, Epidermophyton-Arten, wie Epidermophyton floccosum, Aspergillus-Arten, wie Aspergillus niger und Aspergillus fumigatus, Trichophyton-Arten, wie Trichophyton mentagrophytes, Microsporon-Arten, wie Microsporon felineum sowie Torulopsis-Arten, wie Torulopsis glabrata. Die Aufzählung dieser Mikroorganismen stellt keinesfalls eine Beschränkung der bekämpfbaren Keime dar, sondern hat nur erläuternden Charakter.The compounds of formula (I) which can be used according to the invention and their acid addition salts have antimicrobial, in particular strong antifungal, effects. They have a very broad antimycotic activity spectrum in particular against dermatophytes and yeasts as well as bi - phasic mushrooms, zBgegen Candida species such as Candida albicans, Epidermophyton species such as Epidermophyton floccosum, Aspergillus species such as Aspergillus niger and Aspergillus fumigatus, Trichophyton species such as Trichophyton mentagrophytes, Microsporon species such as Microsporon felineum and Torulopsis species such as Torulopsis glabrata. The enumeration of these microorganisms does not in any way limit the number of germs which can be controlled, but is only of an explanatory nature.

Als Indikationsgebiete in der Humanmedizin können beispielsweise genannt werden:

  • Dermatomykosen und Systemmykosen durch Trichophyton mentagraphytes und andere Trichophytonarten, Mikrosporonarten, Epidermophyton floccosum, Sproßpilze und biphasische Pilze sowie Schimmelpilze hervorgerufen.
Indications for use in human medicine include:
  • Dermatomycoses and system mycoses caused by Trichophyton mentagraphytes and other Trichophyton species, microsporon species, Epidermophyton floccosum, shoots and biphasic fungi as well as molds.

Als Indikationsgebiete in der Tiermedizin können beispielsweise aufgeführt werden:

  • Alle Dermatomykosen und Systemmykosen, insbesondere solche, die durch die obengenannten Erreger hervorgerufen werden.
Indications in veterinary medicine can include the following:
  • All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nicht toxischen, inerten pharmazeutisch geeigneten Trägerstoffen einen oder mehrere erfindungsgemäße Wirkstoffe enthalten oder die aus einem oder mehreren erfindungsgemäßen Wirkstoff bestehen sowie Verfahren zur Herstellung dieser Zubereitungen.The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active compounds according to the invention or which consist of one or more active compounds according to the invention, and methods for producing these preparations.

Zur vorliegenden Erfindung gehören auch pharmazeutische Zubereitungen in Dosierungseinheiten. Dies bedeutet, daß die Zubereitungen in Form einzelner Teile, z.B. Tabletten, Dragees, Kapseln, Pillen, Suppositorien und Ampullen vorliegen, deren Wirkstoffgehalt einem Bruchteil oder einem Vielfachen einer Einzeldosis entspricht. Die Dosierungseinheiten können z.B. 1, 2, 3 oder 4 Einzeldosen oder 1/2, 1/3 oder 1/4 einer Einzeldosis enthalten. Eine Einzeldosis enthält vorzugsweise die Menge Wirkstoff, die bei einer Applikation verabreicht wird und die gewöhnlich einer ganzen, einer halben oder einem Drittel oder einem Viertel einer Tagesdosis entspricht.The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. Tablets, coated tablets, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Unter nicht toxischen, inerten pharmazeutisch geeigneten Trägerstoffen sind feste, halbfeste oder flüssige Verdünnungsmittel, Füllstoffe und Formulierungshilfsmittel jeder Art zu verstehen.Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Als bevorzugte pharmazeutische Zubereitungen seien Tabletten, Dragees, Kapseln, Pillen, Granulate, Suppositorien, Lösungen, Suspensionen und Emulsionen, Pasten, Salben, Gele, Cremes, Lotions, Puder und Sprays genannt.Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tabletten, Dragees, Kapseln, Pillen und Granulate können den oder die Wirkstoffe neben den üblichen Trägerstoffen enthalten, wie (a) Füll- und Streckmittel, z.B. Stärken, Milchzucker, Rohrzucker, Glukose, Mannit und Kieselsäure, (b) Bindemittel, z.B. Carboxymethylcellulose, Alginate, Gelatine, Polyvinylpyrrolidon, (c) Feuchtehaltemittel, z.B. Glycerin, (d) Sprengmittel, z.B. Agar-Agar, Calciumcarbonat und Natriumcarbonat, (e) Lösungsverzögerer, z.B. Paraffin und (f) Resorptionsbeschleuniger, z.B. quaternäre Ammoniumverbindungen, (g) Netzmittel, z.B. Cetylalkohol, Glycerinmonostearat, (h) Adsorptionsmittel, z.B. Kaolin und Bentonit und (i) Gleitmittel, z.B. Talkum, Calcium- und Magnesiumstearat und feste Polyethylenglykole oder Gemische der unter (a) bis (i) aufgeführten Stoffe.Tablets, coated tablets, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, (c) moisture retention agents, e.g. Glycerin, (d) disintegrant, e.g. Agar, calcium carbonate and sodium carbonate, (e) solution retarders, e.g. Paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite and (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

Den Tabletten, Dragees, Kapseln, Pillen und Granulate können mit den üblichen gegebenenfalls Opakisierungsmittel enthaltenden Überzügen und Hüllen versehen sein und auch so zusammengesetzt sein, daß sie den oder die Wirkstoffe nur oder bevorzugt in einem bestimmten Teil der Intestinaltraktes, gegebenenfalls verzögert abgeben, wobei als Einbettungsmassen, z.B. Polymersubstanzen und Wachse verwendet werden können.The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and casings optionally containing opacifying agents and can also be composed such that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, where as Embedding materials, e.g. Polymer substances and waxes can be used.

Der oder die Wirkstoffe können gegebenenfalls mit einem oder mehreren der oben angegebenen Trägerstoffen auch in mikroverkapselter Form vorliegen.The active ingredient (s) can optionally also be in microencapsulated form with one or more of the above-mentioned excipients.

Suppositorien können neben dem oder den Wirkstoffen die üblichen wasserlöslichen oder wasserunlöslichen Trägerstoffe enthalten, z.B. Polyethylenglykole, Fette, z.B. Kakaofett und höhere Ester (z.B. C 14-Alkohol mit C16-Fettsäure) oder Gemische dieser Stoffe.In addition to the active substance or substances, suppositories can contain the usual water-soluble or water-insoluble carriers, for example polyethylene glycols, fats, for example K akaofat and higher esters (for example C 14 alcohol with C 16 fatty acid) or mixtures of these substances.

Salben, Pasten, Cremes oder Gele können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z.B. tierische und pflanzliche Fette, Wachse, Paraffine, Stärke, Tragant, Cellulosederivate, Polyethylenglykole, Silicone, Bentonite, Kieselsäure, Talkum oder Zinkoxid oder Gemische dieser Stoffe.In addition to the active ingredient (s), ointments, pastes, creams or gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc or zinc oxide or mixtures of these substances.

Puder und Sprays können neben dem oder den Wirkstoffen die üblichen Trägerstoffe enthalten, z.B. Milchzucker, Talkum Kieselsäure, Aluminiumhydroxid, Calciumsilikat und Polyamidpulver oder Gemische dieser Stoffe, Sprays können zusätzlich die üblichen Treibmittel z.B. Chlorfluorkohlenwasserstoffe enthalten.Powders and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, sprays can additionally contain the usual blowing agents e.g. Contain chlorofluorocarbons.

Lösungen und Emulsionen können nebem dem oder den Wirkstoffen die üblichen Trägerstoffe wie Lösungsmittel, Lösungsvermittler und Emulgatoren, z.B. Wasser, Ethylalkohol, Isopropylalkohol, Ethylcarbonat, Ethylacetat, Benzylalkohol, Benzylbenzoat, Propylenglykol, 1,3-Butylenglykol, Dimethylformamid, Öle, insbesondere Baumwollsaatöl, Erdnußöl, Maiskeimöl, Olivenöl, Ricinusöl und Sesamöl, Glycerin, Glycerinformal, Tetrahydrofurfurylalkohol, Polyethylenglykole und Fettsäureester des Sorbitans oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as solvents, solubilizers and emulsifiers, for example water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially tree woolen oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

Zur parenteralen Applikation können die Lösungen und Emulsionen auch in steriler und blutisotonischer Form vorliegen.For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form.

Suspensionen können neben dem oder den Wirkstoffen die üblichen Trägerstoffe wie flüssige Verdünnungsmittel, z.B. Wasser, Ethylalkohol, Propylenglykol, Suspendiermittel, z.B. ethoxylierte Isostearylalkohole, Polyoxyethylensorbit- und Sorbitanester, mikrokristalline Cellulose, Aluminiummetahydroxid, Bentonit, Agar-Agar und Tragant oder Gemische dieser Stoffe enthalten.In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth or mixtures of these substances.

Die genannten Formulierungsformen können auch Färbemittel, Konservierungsstoffe sowie geruchs- und geschmacksverbessernde Zusätze, z.B. Pfefferminzöl und Eukalyptusöl und Süßmittel, z.B. Saccharin enthalten.The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Contain saccharin.

Die therapeutisch wirksamen Verbindungen sollen in den oben aufgeführten pharmazeutischen Zubereitungen vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5, vorzugsweise von etwa 0,5 bis 95 Gew.-% der Gesamtmischung vorhanden sein.The therapeutically active compounds should be present in the pharmaceutical preparations listed above preferably in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95% by weight of the total mixture.

Die oben aufgeführten pharmazeutischen Zubereitungen können außer den erfindungsgemäßen Wirkstoffen auch weitere pharmazeutische Wirkstoffe enthalten.In addition to the active substances according to the invention, the pharmaceutical preparations listed above can also contain further pharmaceutical active substances.

Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirkstoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

Zur vorliegenden Erfindung gehören auch die Verwendung der erfindungsgemäßen Wirkstoffe sowie von pharmazeutischen Zubereitungen, die einen oder mehrere erfindungsgemäße Wirkstoffe enthalten, in der Human-und Veterinärmedizin zur Verhütung, Besserung und/ oder Heilung der oben angeführten Erkrankungen.The present invention also includes the use of the active compounds according to the invention and of pharmaceutical preparations which contain one or more active compounds according to the invention in human and veterinary medicine for preventing, ameliorating and / or curing the diseases mentioned above.

Die Wirkstoffe oder die pharmazeutischen Zubereitungen können lokal, oral, parenteral, intraperitoneal und/ oder rectal, vorzugsweise parenteral, insbesondere intravenös appliziert werden.The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedizin als vorteilhaft erwiesen, den oder die erfindungsgemäßen Wirkstoffe in Gesamtmengen von etwa 10 bis etwa 300, vorzugsweise 50 bis 200 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben zur Erzielung der gewünschten Ergebnisse zu verabreichen.In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 10 to about 300, preferably 50 to 200 mg / kg of body weight per 24 hours, optionally in the form of several individual doses to achieve the desired results.

Es kann jedoch erforderlich sein, von denen genannten Dosierungen abzuweichen und zwar in Abhängigkeit von der Art und dem Körpergewicht des zu behandelnden Objekts,der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. So kann es in einigen Fällen ausreichens sein, mit weniger als der obengenannten Menge Wirkstoff auszukommen, während in anderen Fällen die oben angeführte Wirkstoffmenge überschritten werden muß. Die Festlegung der jeweils erforderlichen opitmalen Dosierung und Applikationsart der Wirkstoffe kann durch jeden Fachmann aufgrund seines Fachwissens leicht erfolgen.However, it may be necessary to deviate from the dosages mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease Type of preparation and application of the drug as well as the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded. The determination of the required optimal dosage and type of application of the active ingredients can easily be made by any specialist on the basis of his specialist knowledge.

HerstellungsbeispieleManufacturing examples Beispiel 1example 1

Figure imgb0018
Zu einer Lösung von 0,11 g (0,047 Mol) Natrium in 30 ml n-Propanol werden bei Raumtemperatur unter Rühren 3,6 g (0,052 Mol) 1,2,4-Triazol gegeben. Man erhitzt auf Rückflußtemperatur und versetzt mit einer Lösung von 2-(4-Chlorphenyl)-2-[2-(1,2,4-triazol-1-yl)-prop-2-yl]-oxiran in 20 ml n-Propanol. Das Reaktionsgemisch wird 15 Stunden unter Rückfluß erhitzt, danach abgekühlt und auf Wasser gegeben. Man extrahiert mit Methylenchlorid, trocknet die organische Phase über Natriumsulfat und engt ein. Der Rückstand wird säulenchromatographisch (Kieselgel; Chloroform : Methanol = 9:1) gereinigt. Man erhält 3,7 g (24,2 % der Theorie) 2-(4-Chlorphenyl)-1,3-di-(1,2,4-triazol-1-yl)-3-methyl-2-butanol vom Schmelzpunkt 114°C.
Figure imgb0018
 3.6 g (0.052 mol) of 1,2,4-triazole are added to a solution of 0.11 g (0.047 mol) of sodium in 30 ml of n-propanol at room temperature with stirring. The mixture is heated to the reflux temperature and a solution of 2- (4-chlorophenyl) -2- [2- (1,2,4-triazol-1-yl) prop-2-yl] oxirane in 20 ml of n- Propanol. The reaction mixture is refluxed for 15 hours, then cooled and poured into water. The mixture is extracted with methylene chloride, the organic phase is dried over sodium sulfate and concentrated. The residue is purified by column chromatography (silica gel; chloroform: methanol = 9: 1). 3.7 g (24.2% of theory) of 2- (4-chlorophenyl) -1,3-di- (1,2,4-triazol-1-yl) -3-methyl-2-butanol are obtained Melting point 114 ° C.

Herstellung des AusgangsproduktesManufacture of the starting product

Figure imgb0019
Figure imgb0019

9,6 g (0,044 Mol) Trimethylsulfoniumodid werden unter Stickstoffatmosphäre in 9,6 g (0,118 Mol) Dimethylsulfat gelöst. Bei Raumtemperatur gibt man 5,2 g (0,044 Mol) Kalium-tert.-butylat zu und läßt 6 Stunden bei Raumtemperatur nachrühren. Anschließend wird bei Raumtemperatur eine Lösung von 9,9 g (0,0397 Mol) 4-Chlorphenyl-[2-(1,2,4-triazol-1-yl)-prop-2-yl]-keton in 16 ml Tetrahydrofuran zugetropft. Man läßt das Reaktionsgemisch 15 Stunden bei Raumtemperatur und 4 Stunden unter Rückfluß nachrühren, kühlt ab und filtriert. Das Filtrat wird im Vakuum eingeengt, der Rückstand auf Wasser gegeben und mit Methylenchlorid extrahiert. Die organische Phase wird über Natriumsulfat getrocknet und im Vakuum eingeengt. Man erhält 10,4 g (100 % der Theorie) 2-(4-Chlorphenyl-2-[2-(1,2,4-triazol-i-yl)-prop-2-yl]-oxiran vom Brechungsindex

Figure imgb0020
= 1,5388.
Figure imgb0021
 9.6 g (0.044 mol) of trimethylsulfonium iodide are dissolved in 9.6 g (0.118 mol) of dimethyl sulfate under a nitrogen atmosphere. 5.2 g (0.044 mol) of potassium tert-butoxide are added at room temperature and the mixture is stirred for 6 hours at room temperature. A solution of 9.9 g (0.0397 mol) of 4-chlorophenyl- [2- (1,2,4-triazol-1-yl) prop-2-yl] ketone in 16 ml of tetrahydrofuran is then added at room temperature dripped. The reaction mixture is left to stir for 15 hours at room temperature and 4 hours under reflux, cooled and filtered. The filtrate is concentrated in vacuo, the residue is poured into water and extracted with methylene chloride. The organic phase is dried over sodium sulfate and concentrated in vacuo. 10.4 g (100% of theory) of 2- (4-chlorophenyl-2- [2- (1,2,4-triazol-i-yl) prop-2-yl] oxirane of refractive index are obtained
Figure imgb0020
 = 1 , 5388.
Figure imgb0021

80 g (0,31 Mol) (2-Brom-prop-2-yl)-4-chlorphenyl-keton, 26,9 g (0,39 Mol) 1,2,4-Triazol und 53,8 g (0,39 Mol) Kaliumcarbonat werden in 350 ml Aceton 6 Stunden unter Rückfluß erhitzt. Man läßt abkühlen, filtriert und engt das Filtrat im Vakuum ein. Der Rückstand wird in Methylenchlorid aufgenommen, mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt. Der Rückstand wird aus Diisopropylether umkristallisiert.80 g (0.31 mol) (2-bromo-prop-2-yl) -4-chlorophenyl ketone, 26.9 g (0.39 mol) 1,2,4-triazole and 53.8 g (0 , 39 mol) of potassium carbonate are heated under reflux in 350 ml of acetone for 6 hours. The mixture is allowed to cool, filtered and the filtrate is concentrated in vacuo. The residue is taken up in methylene chloride, washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is recrystallized from diisopropyl ether.

Man erhält 19,9 g (25,7 % der Theorie) 4-Chlorphenyl-[2-(1,2,4-triazol-1-yl)-prop-2-yl]-keton vom Schmelzpunkt 111°C.

Figure imgb0022
19.9 g (25.7% of theory) of 4-chlorophenyl- [2- (1,2,4-triazol-1-yl) prop-2-yl] ketone with a melting point of 111 ° C. are obtained.
Figure imgb0022

65,5 g (0,36 Mol) 4-Chlorphenyl-isopropyl-keton werden in 200 ml Chloroform gelöst und mit 1 ml Bromwasserstoff/Eisessig versetzt. Man läßt dann bei 30°C 57,5 g (0,36 Mol) Brom langsam zutropfen und 30 Minuten bei Raumtemperatur nachrühren. Man engt im Vakuum ein und erhält 86,6 g (92 % der Theorie) rohes (2-Brom-prop-2-yl)-4-chlorphenyl-keton als öl, das direkt weiter umgesetzt wird.65.5 g (0.36 mol) of 4-chlorophenyl isopropyl ketone are dissolved in 200 ml of chloroform and 1 ml of hydrogen bromide / glacial acetic acid is added. 57.5 g (0.36 mol) of bromine are then slowly added dropwise at 30 ° C. and stirring is continued for 30 minutes at room temperature. The mixture is concentrated in vacuo and 86.6 g (92% of theory) of crude (2-bromo-prop-2-yl) -4-chlorophenyl ketone are obtained as an oil, which is directly reacted further.

Beispiel 2Example 2

Figure imgb0023
Zu einer Lösung von 0,1 g (0,043 Mol) Natrium in 30 ml n-Propanol werden bei Raumtemperatur unter Rühren 3,6 g (0,052 Mol) 1,2,4-Triazol gegeben. Man versetzt danach mit einer Lösung von 13,2 g (0,043 Mol) 2-(4-Chlorphenyl- tert.-butyl)-2-[1-(1,2,4-triazol-1-yl)-ethyl]-oxiran in 20 ml n-Propanol. Das Reaktionsgemisch wird 20 Stunden unter Rückfluß erhitzt, dann abgekühlt und auf 300 ml Wasser gegeben. Man extrahiert mit Methylenchlorid, wäscht die Methylenchloridphase mit Wasser, trocknet über Natriumsulfat und engt im Vakuum ein. Der Rückstand wird säulenchromatographisch (Kieselgel; Essigester : Ether = 3:1) gereinigt. Man erhält 4 g (24,8 % der Theorie) 1-(4-Chlorphenyl)-2,2-dimethyl-3-(1,2,4-triazol-1-yl)-methyl)-4-(1,2,4-triazol-1-yl)-3-pentanol vom Schmelzpunkt 59°C.
Figure imgb0023
 3.6 g (0.052 mol) of 1,2,4-triazole are added to a solution of 0.1 g (0.043 mol) of sodium in 30 ml of n-propanol at room temperature with stirring. A solution of 13.2 g (0.043 mol) of 2- (4-chlorophenyl-tert-butyl) -2- [1- (1,2,4-triazol-1-yl) ethyl] - is then added. oxirane in 20 ml of n-propanol. The reaction mixture is refluxed for 20 hours, then cooled and poured into 300 ml of water. It is extracted with methylene chloride, the methylene chloride phase is washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is purified by column chromatography (silica gel; ethyl acetate: ether = 3: 1). 4 g (24.8% of theory) of 1- (4-chlorophenyl) -2,2-dimethyl-3- (1,2,4-triazol-1-yl) methyl) -4- (1, 2,4-triazol-1-yl) -3-pentanol with a melting point of 59 ° C.

Herstellung des AugangsproduktesProduction of the initial product

Figure imgb0024
Eine Lösung von 9,8 g (0,77 Mol) Dimethylsulfat und 5,3 g (0,085 Mol) Dimethylsulfid in 50 ml Acetonitril läßt man 5 Tage bei Raumtemperatur rühren. Anschließend läßt man bei Raumtemperatur eine Lösung von 13 g (0,044 Mol) t4-Chlorphenyl-tert.-butyl)-/1-(1,2,4-triazol-1-yl)-ethy!7-keton in 20 ml Acetonitril zutropfen. Bei gleicher Temperatur trägt man 4,8 g (0,088 Mol) Natriummethylat ein, läßt 20 Stunden nachrühren und engt anschließend im Vakuum ein. Der Rückstand wird mit einem Gemisch aus 35 ml Essigester und 25 ml Wasser über Nacht verrührt. Die organische Phase wird abgetrennt, über Natriumsulfat getrocknet und im Vakuum eingeengt. Man erhält 13,2 g (98,2 % der Theorie) 2-(4-Chlorphenyl-tert.-butyl)-2-[1-(1,2;4-triazol-1-yl)-ethyl]-oxiran vom Brechungsindex
Figure imgb0025
= 1,5431.
Figure imgb0024
 A solution of 9.8 g (0.77 mol) of dimethyl sulfate and 5.3 g (0.085 mol) of dimethyl sulfide in 50 ml of acetonitrile is allowed to stir for 5 days at room temperature. A solution of 13 g (0.044 mol) of t4-chlorophenyl-tert-butyl) - / 1- (1,2,4-triazol-1-yl) ethyl 7-ketone in 20 ml of acetonitrile is then left at room temperature drop. At the same temperature, 4.8 g (0.088 mol) of sodium methylate are added, the mixture is left to stir for 20 hours and then concentrated in vacuo. The residue is stirred with a mixture of 35 ml of ethyl acetate and 25 ml of water overnight. The organic phase is separated off, dried over sodium sulfate and concentrated in vacuo. 13.2 g (98.2% of theory) of 2- (4-chlorophenyl-tert-butyl) -2- [1- (1,2; 4-triazol-1-yl) ethyl] oxirane are obtained from the refractive index
Figure imgb0025
 = 1.5431.

In entsprechender Weise werden die folgenden Verbindungen der allgemeinen Formel

Figure imgb0026
erhalten:
Figure imgb0027
Figure imgb0028
 In a corresponding manner, the following compounds of the general formula
Figure imgb0026
 receive:
Figure imgb0027
Figure imgb0028

Formen A und B: Die beiden möglichen geometrischen Isomeren EntsprechendBeispiel 1 und entsprechend den angegebenen Verfahrensbedingungen werden die folgenden Zwischenprodukte der allgemeinen Formel

Figure imgb0029
erhalten.
Figure imgb0030
 Forms A and B: The two possible geometric isomers According to Example 1 and according to the specified process conditions, the following intermediates of the general formula
Figure imgb0029
 receive.
Figure imgb0030

Beispiel AExample A Antimykotische in vitro-WirksamkeitIn vitro antifungal activity

Versuchsbeschreibung:
Die in-vitro-Prüfungen wurden im Reihenverdünnungstest mit Keiminokula von durchschnittlich 5 x 104 Keimen/ml Substrat durchgeführt. Als Nährmedium dienten

  • a) für Dermatophyten und Schimmelpilze:
    Sabourand's milieu d'epreuve
  • b) für Hefen:
    Fleischextrakt-Traubenzucker-Bouillon.
Experiment description:
The in-vitro tests were carried out in a serial dilution test with germinocula of an average of 5 x 10 4 germs / ml of substrate. Served as a nutrient medium
  • a) for dermatophytes and molds:
    Sabourand's milieu d'epreuve
  • b) for yeasts:
    Meat extract and dextrose broth.

Die Bebrütungstemperatur betrug 20°C, die Bebrütungsdauer lag bei 24 bis 96 Stunden bei Hefen und 96 Stunden bei Dermatophyten und Schimmelpilzen.The incubation temperature was 20 ° C, the incubation period was 24 to 96 hours for yeasts and 96 hours for dermatophytes and molds.

In diesem Test zeigen insbesondere die Verbindungen der Herstellungsbeispiele 3, 5, 6, 8, 9 und 10 ein gutes antimykotisches Wirkungsspektrum.

Figure imgb0031
In this test, the compounds of Preparation Examples 3, 5, 6, 8, 9 and 10 in particular show a good spectrum of antifungal activity.
Figure imgb0031

Beispiel BExample B Antimykotische in-vitro-Wirksamkeit (oral) bei MäusecandidoseIn vitro antifungal efficacy (oral) in mouse candidiasis Versuchsbeschreibung:Experiment description:

Mäuse vom Typ SPF-CF1 wurden intravenös mit 1-2 x 106 logarthmisch wachsenden Candida-Zellen, die in physiologischer Kochsalzlösung suspendiert werden, infiziert. Eine Stunde vor und sieben Stunden nach der Infektion werden die Tiere mit jeweils 10-50 mg/kg Körpergewicht der Präparate oral behandelt.Mice of the type SPF-CF 1 were infected intravenously with 1-2 x 10 6 logarthmically growing Candida cells, which are suspended in physiological saline. One hour before and seven hours after the infection, the animals are treated orally with 10-50 mg / kg body weight of the preparations.

Erebnis:Result:

Unbehandelte Tiere starben 3 bis 6 Tage post infektionem. Die überlebensrate am 6. tag post infektionem betrug bei unbehandelten Kontrolltieren etwa 5 %. In diesem Test zeigten z.B., die Verbindungen der Herstellungsbeispiele 1, 3, 4 und 5 eine gute antimykotische Wirkung.Untreated animals died 3 to 6 days after infection. The survival rate on the 6th day after infection was about 5% in untreated control animals. For example, in this test, the compounds of Preparation Examples 1, 3, 4 and 5 showed good antifungal activity.

ZeichenerklärungExplanation of symbols

  • +++++ = sehr gute Wirkung = 90 % Überlebende am 6. Tag p.i.+++++ = very good effect = 90% survivors on the 6th day p.i.
  • ++++ = gute Wirkung = 80 % Überlebende am 6. Tag p.i.++++ = good effect = 80% survivors on the 6th day p.i.
  • +++ = Wirkung = 60 % Überlebende am 6. Tag p.i.+++ = effect = 60% survivors on day 6 p.i.
  • ++ = schwache Wirkung = 40 % Überlebende am 6. Tag p.i.++ = weak effect = 40% survivors on day 6 p.i.
  • + = Spur Wirkung =+ = Trace effect =
  • k.W. = keine Wirkungk.W. = no effect

Figure imgb0032
Figure imgb0032

Beispiel/FormulierungenExample / wording 1. Lösung1. Solution

Figure imgb0033
Figure imgb0033

2. Creme2. Cream

Figure imgb0034
Figure imgb0034

Claims (9)

1. Substituierte Diazolylalkyl-carbinole der allgemeinen Formel
Figure imgb0035
in welcher A für ein Stickstoffatom oder die CH-Gruppe steht, B für ein Stickstoffatom oder die CH-Gruppe steht, X für Wasserstoff oder Alkyl steht, Y für Alkyl steht, sowie auch für Alkenyl, Alkinyl oder gegebenenfalls substituiertes Benzyl steht, wenn X für Wasserstoff steht und R für gegebenenfalls substituiertes Phenyl und die Gruppierung
Figure imgb0036
steht, wobei Alk1 für Alkyl steht, Alk2 für Alkyl steht, oder Alk 1 und Alk 2 gemeinsam für einen cycloaliphatischen Ring stehen und R 1 für Alkyl, Alkenyl oder für jeweils gegebenenfalls substituiertes Phenyl, Phenylalkyl, Phenoxy, Phenylthio, Phenoxyalkyl, Phenylthioalkyl, Benzyloxy oder Benzylthio steht,
und deren pyhysiologisch verträglichen Säureadditionssalze. 1. Substituted diazolylalkyl carbinols of the general formula
Figure imgb0035
 in which A represents a nitrogen atom or the CH group, B represents a nitrogen atom or the CH group, X represents hydrogen or alkyl, Y stands for alkyl, and also stands for alkenyl, alkynyl or optionally substituted benzyl, if X stands for hydrogen and R represents optionally substituted phenyl and the grouping
Figure imgb0036
 stands where Al k 1 represents alkyl, A lk 2 represents alkyl, or Alk 1 and Alk 2 together represent a cycloaliphatic ring and R 1 represents alkyl, alkenyl or optionally substituted phenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy or benzylthio,
and their pyhysiologically acceptable acid addition salts. 2. Verbindungen der Formel (I) in Anspruch 1, in der A für ein Stickstoffatom oder die CH-Gruppe; B für ein Stickstoffatom oder die CH-Gruppe; X für Wasserstoff und geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen; Y für geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen; sowie für den Fall, daß X für Wasserstoff steht, auch für geradkettiges oder verzweigtes Alkenyl und Alkinyl mit jeweils 3 bis 6 Kohlenstoffatomen sowie für gegebenenfalls einfach bis dreifach gleich oder verschieden im Phenylteil substituiertes Benzyl, wobei als Substituenten genannt seien: Halogen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy und Alkylthio mit jeweils 1 bis 4 Kohlenstoffatomen, Halogenalkyl, Halogenalkoxy und Halogenalkylthio mit jeweils 1 bis 2 Kohlenstoff- und 1 bis 5 gleichen oder verschiedenen Halogenatomen, wie vorzugsweise Fluor- und Chloratomen, Nitro und Cyano; R für gegebenenfalls einfach bis dreifach, gleich oder verschieden substituiertes Phenyl, wobei als Substituenten vorzugsweise genannt seien: Halogen, Alkyl mit 1 bis 4 Kohlenstoffatomen, Alkoxy und Alkylthio mit jeweils 1 bis 4 Kohlenstoffatomen, Halogenalkyl, Halogenalkoxy und Halogenalkylthio mit jeweils 1 bis 2 Kohlenstoff- und 1 bis 5 gleichen oder verschiedenen Halogenatomen, wie vorzugsweise Fluor- und Chloratomen, Nitro, Cyano, Hydroxy, Hydroxycarbonyl, Alkoxcarbonyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Hydroximinoalkyl mit 1 bis 4 Kohlenstoffatomen, Alkoximinoalkyl mit 1 bis 4 Kohlenstoffatomen, in jedem Alkylteil, sowie jeweils gegebenenfalls durch Halogen und/oder Alkyl mit 1 bis 2 Kohlenstoffatomen substituiertes Phenyl, Phenoxy, Benzyl und Benzyloxy; R steht ferner vorzugsweise für die Gruppierung
Figure imgb0037
wobei Alk1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht; Alk2 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht; Alk und Alk2 gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, für einen 3- bis 7-gliedrigen cycloaliphatischen Ring stehen; und R für geradkettiges oder verzweigtes Alkyl mit 1 bis 6 Kohlenstoffatomen, für Alkenyl mit 2 bis 4 Kohlenstoffatomen, sowie für jeweils gegebenenfalls im Phenylteil einfach bis dreifach, gleich oder verschieden substituiertes Phenyl, Phenylalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Phenoxy, Phenylthio, Phenoxyalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Phenylthioalkyl mit 1 bis 4 Kohlenstoffatomen im Alkylteil, Benzyloxy und Benzylthio steht, wobei als Substituenten vorzugsweise die bei R bereits genannten Phenylsubstituenten in Frage kommen. 2. Compounds of formula (I) in claim 1, in which A represents a nitrogen atom or the CH group; B represents a nitrogen atom or the CH group; X represents hydrogen and straight-chain or branched alkyl having 1 to 6 carbon atoms; Y represents straight-chain or branched alkyl having 1 to 6 carbon atoms; and in the event that X stands for hydrogen, also for straight-chain or branched alkenyl and alkynyl each with 3 to 6 carbon atoms and for benzyl which is optionally monosubstituted to trisubstituted identically or differently in the phenyl part, where the following may be mentioned as substituents: halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 4 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each with 1 to 2 carbon and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro and cyano; R for phenyl which is monosubstituted to trisubstituted by identical or different substituents, the preferred substituents being: halogen, alkyl having 1 to 4 carbon atoms, alkoxy and alkylthio each having 1 to 4 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each having 1 to 2 carbon - and 1 to 5 identical or different halogen atoms, such as preferably fluorine and chlorine atoms, nitro, cyano, hydroxy, hydroxycarbonyl, alkoxcarbonyl with 1 to 4 carbon atoms in the alkyl part, hydroximinoalkyl with 1 to 4 carbon atoms, alkoximinoalkyl with 1 to 4 carbon atoms, in each Alkyl part, and also phenyl optionally substituted by halogen and / or alkyl having 1 to 2 carbon atoms, Phenoxy, benzyl and benzyloxy; R also preferably represents the grouping
Figure imgb0037
 in which Alk 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms; Alk 2 represents straight-chain or branched alkyl having 1 to 4 carbon atoms; Alk and Alk 2 together with the carbon atom to which they are attached represent a 3- to 7-membered cycloaliphatic ring; and R for straight-chain or branched alkyl having 1 to 6 carbon atoms, for alkenyl having 2 to 4 carbon atoms, and for phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxyalkyl, phenylthio or phenoxyalkyl which is monosubstituted to trisubstituted in the phenyl part in each case, mono- or trisubstituted in the same way or differently with 1 to 4 carbon atoms in the alkyl part, Phenylthioalkyl having 1 to 4 carbon atoms in the alkyl part, benzyloxy and benzylthio, the phenyl substituents already mentioned for R being preferred as substituents. 3. Verbindungen der Formel (I) in Anspruch 1, in der A für ein Stickstoffatom oder die CH-Gruppe steht; B für ein Stickstoffatom oder die CH-Gruppe steht; X für Wasserstoff und geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht; Y für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht, sowie für den Fall, daß X für Wasserstoff steht, auch für Allyl, Methylallyl, Propargyl, Methylpropargyl oder für gegebenenfalls einfach bis zweifach, gleich oder verschieden im Phenylteil substituiertes Benzyl steht, wobei als Substituenten genannt seien: Fluor, Chlor, Brom, Methyl, Isopropyl, tert.-Butyl, Methoxy, Methylthio, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Nitro und Cyano; R für gegebenenfalls einfach bis zweifach, gleich oder verschieden substituiertes Phenyl steht, wobei als Substituenten genannt seien: Fluor, Chlor, Brom, Methyl, Isopropyl, tert.-Butyl, Methoxy, Methylthio, Trifluormethyl, Trifluormethoxy, Trifluormethylthio, Nitro, Cyano, Hydroxy, Hydroxycarbonyl, Methoxycarbonyl, Ethoxycarbonyl, Hydroximinomethyl, 1-Hydroximinoethyl, Methoximinomethyl, 1-Methoximinoethyl, sowie jeweils gegebenenfalls durch Fluor, Chlor, Methyl substituiertes Phenyl, Phenoxy, Benzyl und Benzyloxy; ferner R für die Gruppierung
Figure imgb0038
steht, wobei Alk1 für Methyl oder Ethyl steht; Alk2 für Methyl oder Ethyl steht; Alk1 und Alk2 gemeinsam mit dem Kohlenstoffatom, an das sie gebunden sind, für Cyclobutyl, Cyclopentyl oder Cyclohexyl stehen; und R für Methyl, Ethyl, n-Propyl, i-Propyl, n-Butyl, Neopentyl, sowie für jeweils gegebenenfalls im Phenylteil einfach bis zweifach, gleich oder verschieden substituiertes Phenyl, Benzyl, Phenethyl, Phenoxy, Phenylthio, Phenoxymethyl, Phenoxy- ethyl, Phenylthiomethyl, Phenylthioethyl, Benzyloxy oder Benzylthio steht, wobei als Substituenten die bei R bereits genannten Phenylsubstituenten in Frage kommen. 3. Compounds of formula (I) in claim 1, in which A represents a nitrogen atom or the CH group; B represents a nitrogen atom or the CH group; X represents hydrogen and straight-chain or branched alkyl having 1 to 4 carbon atoms; Y stands for straight-chain or branched alkyl with 1 to 4 carbon atoms, and for the case that X stands for hydrogen, also for allyl, methylallyl, propargyl, methylpropargyl or for benzyl which is optionally monosubstituted to disubstituted in the phenyl part, where the following may be mentioned as substituents: Fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro and cyano; R represents phenyl which is monosubstituted or disubstituted, identically or differently, where the following may be mentioned as substituents: fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, cyano, hydroxy , Hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroximinomethyl, 1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl, and in each case optionally substituted by fluorine, chlorine, methyl, phenyl, phenoxy, benzyl and benzyloxy; furthermore R for the grouping
Figure imgb0038
 stands where Alk 1 represents methyl or ethyl; A lk 2 represents methyl or ethyl; Alk 1 and Alk 2 together with the carbon atom to which they are attached represent cyclobutyl, cyclopentyl or cyclohexyl; and R is methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl, and substituted in each case optionally substituted once in the phenyl moiety up to two times by identical or different phenyl, benzyl, phenethyl, phenoxy, phenylthio, phenoxymethyl, P henoxy- ethyl , Phenylthiomethyl, phenylthioethyl, benzyloxy or benzylthio, where the phenyl substituents already mentioned for R are suitable as substituents. 4. 2-(4-Chlorphenyl)-1,3-di-(1,2,4-triazol-1-yl)-3-methyl-2-butanol.4. 2- (4-chlorophenyl) -1,3-di- (1,2,4-triazol-1-yl) -3-methyl-2-butanol. 5. 2-(4-Fluorphenyl)-1,3-di-(-1,2,4-triazol-1-yl)-3-methyl-2-butanol.5. 2- (4-fluorophenyl) -1,3-di - (- 1,2,4-triazol-1-yl) -3-methyl-2-butanol. 6. 2-Phenyl-1,3-di-(1,2,4-triazol-1-yl)-3-methyl-2-butanol.6. 2-phenyl-1,3-di- (1,2,4-triazol-1-yl) -3-methyl-2-butanol. 7. Azolylketone der allgemeinen Formel
Figure imgb0039
in welcher X1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht, Y1 für geradkettiges oder verzweigtes Alkyl mit 1 bis 4 Kohlenstoffatomen steht und B und R die oben angegebene Bedeutung haben. 7. Azolyl ketones of the general formula
Figure imgb0039
 in which X 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms, Y 1 represents straight-chain or branched alkyl having 1 to 4 carbon atoms and B and R have the meaning given above. 8. Substituierte Diazolylalkyl-carbinole der allgemeinen Formel
Figure imgb0040
in welcher A für ein Stickstoffatom oder die CH-Gruppe steht, B für ein Stickstoffatom oder die CH-Gruppe steht, X für Wasserstoff oder Alkyl steht, Y für Alkyl steht, sowie auch für Alkenyl, Alkinyl oder gegebenenfalls substituiertes Benzyl steht, wenn X für Wasserstoff steht und R für gegebenenfalls substituiertes Phenyl und die Gruppierung
Figure imgb0041
steht wobei Alk1 für Alkyl steht, Alk2 für Alkyl steht, oder Alk1 und Alk2 gemeinsam für einen cycloaliphatischen Ring stehen und R für Alkyl, Alkenyl oder für jeweils gegebenenfalls substituiertes Phenyl, Phenylalkyl, Phenoxy, Phenylthio, Phenoxyalkyl, Phenylthioalkyl, Benzyloxy oder Benzylthio steht,und deren physiologisch verträglichen Säureadditions- salze bei der Behandlung von Mykosen.8. Substituted diazolylalkyl carbinols of the general formula
Figure imgb0040
 in which A represents a nitrogen atom or the CH group, B represents a nitrogen atom or the CH group, X represents hydrogen or alkyl, Y stands for alkyl, and also stands for alkenyl, alkynyl or optionally substituted benzyl, if X stands for hydrogen and R represents optionally substituted phenyl and the grouping
Figure imgb0041
 stands where Alk 1 represents alkyl, Al k 2 represents alkyl, or A lk 1 and Alk 2 together represent a cycloaliphatic ring and R represents alkyl, alkenyl or optionally substituted phenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy or benzylthio, and their physiologically tolerable acid addition salts in the treatment of mycoses. 9. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I) in Anspruch 1, dadurch gekennzeichnet, daß man9. A process for the preparation of compounds of general formula (I) in claim 1, characterized in that
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EP0548553A1 (en) * 1991-11-25 1993-06-30 Takeda Chemical Industries, Ltd. Optically active azole compounds, their production and use
US5495024A (en) * 1991-11-25 1996-02-27 Takeda Chemical Industries Ltd. Optically active azole compounds and their production
EP0667346A2 (en) 1994-02-07 1995-08-16 Eisai Co., Ltd. Azole antifungal agents, process for the preparation there of and intermediates
EP1231210A3 (en) * 1994-02-07 2002-12-04 Eisai Co., Ltd. Azole antifungal agents, processes for the preparation thereof, and intermediates

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JPH0437829B2 (en) 1992-06-22
CA1249592A (en) 1989-01-31
AU2506384A (en) 1984-09-06
CA1245666A (en) 1988-11-29
DE3460971D1 (en) 1986-11-20
HU194189B (en) 1988-01-28
GR79549B (en) 1984-10-30
US5011850A (en) 1991-04-30
CA1239409A (en) 1988-07-19
KR840008020A (en) 1984-12-12
JPS59164778A (en) 1984-09-17
IL71098A (en) 1988-05-31
ATE22887T1 (en) 1986-11-15
HU191254B (en) 1987-01-28
ES530114A0 (en) 1985-04-01
AU6916487A (en) 1987-05-28
AU561701B2 (en) 1987-05-14
EP0120276B1 (en) 1986-10-15
ES8503672A1 (en) 1985-04-01
DE3307218A1 (en) 1984-09-06
DK83684D0 (en) 1984-02-21
DK83684A (en) 1984-09-03
ZA841552B (en) 1984-10-31
IL80726A0 (en) 1987-02-27
IL71098A0 (en) 1984-05-31

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